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Biomedical subjects

T W Stone

Publications and source records attributed to T W Stone.

At least 181 records · Page 10Linked to original sources
PubMed1986

The relative potencies of (-)-2-amino-5-phosphonovalerate and (-)-2-amino-7-phosphonoheptanoate as antagonists of N-methylaspartate and quinolinic acids and repetitive spikes in rat hippocampal slices.

The active (-)-isomers of 2-amino-7-phosphonoheptanoic acid (2-APH) and 2-amino-5-phosphonopentanoic acid (2-APV) have been compared as antagonists of N-methyl-D,L-aspartate (NMDLA) and quinolinic acid on rat hippocampal slices. 2-APH appeared to be about 3 times more potent than 2-APV, though the same ratio was obtained against NMDLA and quinolinic acid. It is suggested that this difference of potency may partly explain the greater anticonvulsant activity of 2-APH. The results are consistent with the view that quinolinate acts at the NMDLA receptor while a differentiation between NMDLA and quinolinic acid is not likely to contribute to the anticonvulsant activities of 2-APH and 2-APV. A 3-fold difference of potency is also shown for (-)-2-APH and (-)-2-APV when blocking bicuculline-induced repetitive spikes in the CA1 region. This would support the involvement of an NMDLA receptor in this phenomenon.

2-Amino-5-phosphonovalerate↗
PubMed1986

Kynurenines do not antagonise GABA in rat hippocampus.

Kynurenine and kynurenic acid are known to produce convulsions in rats and mice and it has been reported that kynurenine can displace GABA from its neuronal binding sites. The present study shows that neither kynurenine nor kynurenic acid are antagonist of GABA when tested on the rat hippocampal slice preparation. It is therefore unlikely that kynurenine seizures result from the blockade of inhibitory neurotransmission.

Animals↗
PubMed1986

The suppression of hippocampal potentials by the benzodiazepine antagonist Ro 15-1788 may be mediated by purines.

The benzodiazepine antagonist Ro 15-1788 has been reported to suppress paired pulse inhibition in the hippocampal slice. It is now shown that the depression of orthodromic synaptic transmission by Ro 15-1788 can be prevented by the adenosine antagonist 8-phenyl-theophylline, or by adenosine deaminase. Since Ro 15-1788 has previously been shown to inhibit adenosine-uptake into rat brain tissue, it is suggested that this property, leading to an accumulation of extracellular adenosine, may underlie its effects on synaptic transmission.

Adenosine↗
PubMed1986

O-phosphohomoserine, a naturally occurring analogue of phosphonate amino acid antagonists, is an N-methyl-D-aspartate (NMDA) antagonist in rat hippocampus.

O-Phosphohomoserine, an analogue of the excitatory amino acid antagonist 2-amino-phosphonovalerate, has been synthesized and tested for activity as an excitatory amino acid antagonist. The tests were carried out on 500 micron thick slices of rat hippocampus superfused in vitro at 30 degrees C. Antidromic and orthodromic potentials were studied in the CA1 region, recording from the pyramidal cell layer. At concentrations of 0.5 and 1 mM the compound produced a weak but significant antagonism of the depression of evoked potentials produced by N-methyl-D-aspartate with no effect on the responses produced by kainic or quisqualic acids. O-Phosphohomoserine was not metabolised by brain homogenates or by alkaline phosphatases. Since O-phosphohomoserine is known to occur naturally in lower organisms, it would be of interest to seek its existence in the animal nervous system.

Animals↗
PubMed1986

Postsynaptic action of kynurenic acid in the rat dentate gyrus.

Quantal analysis was performed on excitatory postsynaptic potentials (EPSP) recorded with intracellular electrodes from granule cells of the rat dentate gyrus, before, during and after the iontophoretic application of kynurenic acid. In this way a reduction in the EPSP caused by kynurenic acid was shown to be accompanied by an appropriate reduction in quantal size whilst the average number of quanta released per impulse was unchanged. The reduction in quantal size parallelled the reduction in the amplitude of the EPSP and is thus consistent with an action of kynurenic acid at a postsynaptic site. In addition, on a number of cells kynurenic acid reduced the depolarization evoked by L-glutamate by an equivalent amount and it is thus proposed that the synaptic transmitter is glutamate-like.

Animals↗
PubMed1986

Effects of topically applied excitatory amino acids on evoked potentials and single cell activity in rat cerebral cortex.

The effect of topically applied excitatory amino acids and related compounds on the somatosensory evoked potential and single cell responses to iontophoretically applied compounds have been studied in the neocortex of urethane anaesthetised rats. N-methyl-aspartate (NMDLA), DL-homocysteic acid (DLH), kainic acid, quinolinic acid and carbachol produced a depression of evoked potential amplitude. L-glutamate and quisqualic acid had no effect. Tetrodotoxin and 2-amino-5-phosphonovaleric acid prevented the effects of NMDLA, but bicuculline and theophylline derivatives did not. There was an apparent desensitisation of the depression of evoked potentials following topical application of NMDLA or DLH, the potentials recovering to control levels during the amino acid application. A second application of amino acid was then ineffective unless applied about 1 h later. Single cell responses to iontophoretically applied NMDLA behaved similarly. There was an apparent cross-desensitisation between NMDLA, DLH and quinolinic acids. The results may indicate a desensitising receptor for amino acids on superficial neocortical neurones.

Administration, Topical↗
PubMed1986

Methylation blockage and other improvements to a comprehensive DNA analysis program.

A comprehensive DNA analysis computer program was described in the second special issue of Nucleic Acids Research on the applications of computers to research on nucleic acids by Stone and Potter (1). Criteria used in designing the program were user friendliness, ability to handle large DNA sequences, low storage requirement, migratability to other computers and comprehensive analysis capability. The program has been used extensively in an industrial-research environment. This paper talks about improvements to that program. These improvements include testing for methylation blockage of restriction enzyme recognition sites, homology analysis, RNA folding analysis, integration of a large DNA database (GenBank), a site specific mutagenesis analysis, a protein database and protein searching programs. The original design of the DNA analysis program using a command executive from which any analytical programs can be called, has proven to be extremely versatile in integrating both developed and outside programs to the file management system employed.

Base Sequence↗
PubMed1986

Activation of thermogenesis of brown fat in rats by baclofen.

Injection of baclofen (0.5-5 micrograms) into the ventromedial hypothalamus (VMH) of anaesthetized rats produced marked increases in the temperature (over 2 degrees C) and thermogenic activity of brown adipose tissue (BAT). These effects were abolished by ganglionic or beta-adrenergic blockade, or denervation of the tissue, but unaffected by hypophysectomy, adrenalectomy or vagotomy. Injections into the hypothalamus close to, but outside the ventromedial hypothalamus did not affect brown adipose tissue. Intravenous administration of baclofen produced similar increases in the temperature of brown adipose tissue, but at larger doses (50-1000 micrograms), and a subcutaneous injection stimulated the metabolic rate in conscious rats. Chronic treatment with baclofen suppressed weight gain and stimulated activity of brown adipose tissue without affecting food intake. These effects of baclofen, which were not mimicked by injections of gamma-aminobutyric acid (GABA), indicate a novel action of baclofen in the ventromedial hypothalamus, leading to marked increases in metabolic rate and body temperature by stimulating sympathetic outflow to brown fat.

Adipose Tissue, Brown↗
PubMed1986

Activity of beta-kainic acid on neocortical neurons in vivo and hippocampal neurons in vitro.

The beta-isomer of kainic acid has been reported to have anticonvulsant activity with a profile suggesting amino acid antagonism. The present study, on neurons in the cerebral cortex of anaesthetised rats or in hippocampal slices, shows that beta-kainate does not antagonise any of the major agonists at amino acid receptors: N-methylaspartate, quisqualic acid or alpha-kainic acid. beta-Kainate does have an excitant action of its own which can be partially reduced by 2-amino-5-phosphonovaleric acid but is unaffected by gamma-D-glutamylglycine. It is blocked completely by kynurenic acid.

2-Amino-5-phosphonovalerate↗
PubMed1985

Differences of neuronal sensitivity to amino acids and related compounds in the rat hippocampal slice.

The perfusion of slices of rat hippocampus with solutions containing N-methyl-DL-aspartic acid (NMA), kainic acid, ibotenic acid or quinolinic acid produced a reduction in the size of antidromically evoked population spikes in the CA1 pyramidal cells or dentate gyrus granule cells. The relative potencies of these compounds on CA1 cells compared with granule cells were kainate 3.65, quinolinate 3.46, NMA 2.19 and ibotenate 1.50. Since the former two compounds are known to show a degree of selective toxicity towards the CA1 cells, whereas NMA and ibotenate do not, these results are consistent with the excitotoxic hypothesis that excitation and neurotoxicity are related.

Amino Acids↗
PubMed1985

Effect of copper on the binding and electrophysiological actions of cyclohexyladenosine.

Since copper ions irreversibly reduce the binding of cyclohexyladenosine (CHA) to rat brain membranes and copper levels are elevated in the brains of seizure-prone mice, the binding of CHA was compared in seizure-prone DBA/2 and control C57 mice. No strain difference was detected in the binding of CHA or the reduction of that binding by copper, although copper was more potent than in rats (IC50 12 microM). In rat hippocampal slices copper did not diminish the inhibitory effects of adenosine or CHA. The results suggest that the seizure sensitivity of DBA/2 mice is not due to an effect of copper on purine receptors and that the copper binding domain of purine receptors is inaccessible to extracellular copper.

Adenosine↗
PubMed1985

Cyclohexyladenosine binding in rat striatum.

N6-Cyclohexyl-[3H]adenosine [( 3H]CHA) binds specifically to rat brain membranes prepared from the caudate-putamen complex with a Kd value of 2.50 +/- 0.39 nM and Bmax of 458 +/- 51 fmol/mg protein. Lesioning the nigrostriatal dopaminergic pathway using 6-hydroxydopamine failed to alter [3H]CHA binding characteristics. Intrastriatal kainate lesions reduced the binding capacity of [3H]CHA by 28% though this was not statistically significant (0.1 less than P greater than 0.05). In kainate-lesioned striata, however, 2-deoxyglucose uptake was reduced by only 39%.

Adenosine↗
PubMed1985

Actions of kynurenic acid and quinolinic acid in the rat hippocampus in vivo.

An iontophoretic study was made of the interaction of kynurenic acid with excitatory amino acids in the hippocampus and with the commissural input from the contralateral hippocampus in the rat. The results showed that kynurenic acid was an effective blocker of synaptic transmission in the hippocampus in vivo, adding further support to the idea that an excitatory amino acid is involved in neurotransmission in this structure. In addition there was an increase in the specificity of kynurenate as an antagonist of excitatory amino acids in the hippocampus compared with neocortex, with much more activity being shown toward the NMDA-preferring rather than the quisqualic acid-preferring receptor. Kynurenic acid was also able to distinguish partially between quinolinic acid and NMDA, supporting the possibility that two types of NMDA/quinolinate receptors exist in the hippocampus.

Amino Acids↗
PubMed1985

The role of kynurenines in diabetes mellitus.

Although different forms of diabetes are known to exist, there are a number of factors which occur in these states all of which would contribute to an increase in the synthesis of the kynurenine metabolites of tryptophan, xanthurenic acid in particular. Conditions giving rise to increased kynurenine metabolism include pregnancy, oral contraceptives, emotional and metabolic stress. We propose a mechanism by which kynurenines act to reduce the concentration of active insulin in plasma and thus give rise to a diabetic state.

Diabetes Mellitus↗
PubMed1985

Baclofen is a potent activator of brown fat metabolism.

The injection of (+/-)-baclofen intravenously or directly into the ventromedial hypothalamus of urethane-anaesthetized rats, produced an activation of brown fat metabolism. This was seen as an increase of brown fat and rectal temperatures, and an increase of GDP binding in brown fat mitochondria. The activation was mediated by the sympathetic supply.

Adipose Tissue, Brown↗